BRIEF SUMMARY-CELEBREX® (celecoxib capsules)
Before prescribing, please consult complete prescribing information.
INDICATIONS AND USAGE
For relief of the signs and symptoms of OA, and of RA in adults.
CONTRAINDICATIONS
CELEBREX is contraindicated in patients with known hypersensitivity to celecoxib.
CELEBREX should not be given to patients who have demonstrated allergic-type
reactions to sulfonamides. CELEBREX should not be given to patients who have
experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other
NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been
reported in such patients (see WARNINGS - Anaphylactoid Reactions, and PRE
CAUTIONS - Preexisting Asthma).
WARNINGS
Gastrointestinal (GI) Effects - Risk of GI Ulceration, Bleeding, and Perforation:
Serious GI toxicity such as bleeding, ulceration, and perforation of the stomach,
small intestine or large intestine, can occur at any time, with or without warning
symptoms, in patients treated with NSAIDs. Minor upper GI problems, such as
dyspepsia, are common and may also occur at any time during NSAID therapy.
Therefore, physicians and patients should remain alert for ulceration and bleeding,
even in the absence of previous GI tract symptoms. Patients should be informed
about the signs and/or symptoms of serious GI toxicity and the steps to take if
they occur. Only 1/5 patients who develop a serious upper GI adverse event on
NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding or perforation,
caused by NSAIDs, appear to occur in approximately 1% of patients treated for
3-6 months, and in about 2-4% of patients treated for one year. These trends
continue thus, increasing the likelihood of developing a serious GI event at some
time during the course of therapy. However, even short-term therapy is not
without risk. It is unclear, at the present time, how the above rates apply to
CELEBREX (see CLINICAL STUDIES - Special Studies in the complete prescrib
ing information). Among 5,285 patients who received CELEBREX in controlled
clinical trials of 1 to 6 months duration (most were 3 month studies) at a daily
dose of 200 mg or more, 2 (0.04%) experienced significant upper GI bleeding, at
14and 22 days after initiation of dosing. Approximately 40% of these 5,285 patients
were in studies that required them to be free of ulcers by endoscopy at study
entry. Thus it is unclear if this study population is representative of the general
population. Prospective, long-term studies required to compare the incidence of
serious, clinically significant upper GI adverse events in patients taking CELEBREX
vs. comparator NSAID products have not been performed. NSAIDs should be pre
scribed with extreme caution in patients with a prior history of ulcer disease or
GI bleeding. Most spontaneous reports of fatal GI events are in elderly or debili
tated patients and therefore special care should be taken in treating this popula
tion. To minimize the potential risk for an adverse GI event, the lowest effective
dose should be used for the shortest possible duration. For high risk patients,
alternate therapies that do not involve NSAIDs should be considered. Studies have
shown that patients with a prior history of peptic ulcer disease and/or GI bleeding
and who use NSAIDs, have a greater than 10-fold higher risk for developing a GI
bleed than patients with neither of these risk factors. In addition to a past history
of ulcer disease, pharmacoepidemiological studies have identified several other
co-therapies or co-morbid conditions that may increase the risk for GI bleeding
such as: treatment with oral corticosteroids, treatment with anticoagulants, longer
duration of NSAID therapy, smoking, alcoholism, older age, and poor general
health status.
Anaphylactoid Reactions: As with NSAIDs in general, anaphylactoid reactions have
occurred in patients without known prior exposure to CELEBREX. In post-mar
keting experience, rare cases of anaphylactic reactions and angioedema have been
reported in patients receiving CELEBREX. CELEBREX should not be given to
patients with the aspirin triad. This symptom complex typically occurs in asth
matic patients who experience rhinitis with or without nasalpolyps, or who exhibit
severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see
CONTRAINDICATIONS and PRECAUTIONS - Preexisting Asthma). Emergency
help should be sought in cases where an anaphylactoid reaction occurs.
Advanced Renal Disease: Treatment with CELEBREX is not recommended.
Pregnancy: In late pregnancy CELEBREX should be avoided because it may cause
premature closure of the ductus arteriosus.
PRECAUTIONS
General: CELEBREX cannot be expected to substitute for corticosteroids or to treat
corticosteroid insufficiency.The pharmacological activity of CELEBREX in reducing
inflammation, and possibly fever, may diminish the utility of these diagnostic signs
in detecting infectious complications of presumed noninfectious, painful condi
tions.
Hepatic Effects: Borderline elevations of one or more liver tests may occur in up
to 15%of patients taking NSAIDs, and notable elevations of ALT or AST (approx
imately three or more times the upper limit of normal) have been reported in
approximately 1%of patients in clinical trials with NSAIDs. These laboratory abnor
malities may progress, may remain unchanged, or may be transient with contin
uing therapy. Rare cases of severe hepatic reactions, including jaundice and fatal
fulminant hepatitis, liver necrosis and hepatic failure (some with fatal outcome)
have been reported with NSAIDs, including CELEBREX. (See ADVERSE REAC
TIONS - post-marketing experience.) Incontrolled clinical trials of CELEBREX, the
incidence of borderline elevations of liver tests was 6%for CELEBREX and 5% for
placebo, and approximately 0.2% of patients taking CELEBREX and 0.3% of
patients taking placebo had notable elevations of ALT and AST. A patient with
symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal
liver test has occurred, should be monitored carefully for evidence of the devel
opment of a more severe hepatic reaction while on therapy with CELEBREX. If
clinical signs and symptoms consistent with liver disease develop, or if systemic
manifestations occur (e.g ., eosinophilia, rash, etc.), CELEBREX should be discon
tinued.
Renal Effects: Long-term administration of NSAIDs has resulted in renal papillary
necrosis and other renal injury. Renal toxicity has also been seen in patients in
whom renal prostaglandins have a compensatory role in the maintenance of renal
perfusion. In these patients, administration of an NSAID may cause a dose
dependent reduction in prostaglandin formation and, secondarily, in renal blood
flow, which may precipitate overt renal decompensation. Patients at greatest risk
of this reaction are those with impaired renal function, heart failure, or liver dys
function, those taking diuretics and ACE inhibitors, and the elderly. Discontinua
tion of NSAID therapy is usually followed by recovery to the pretreatment state.
Clinical trials with CELEBREX have shown renal effects similar to those observed
with comparator NSAIDs. Caution should be used when initiating treatment with
CELEBREX in patients with considerable dehydration. It is advisable to rehydrate
patients first and then start therapy with CELEBREX. Caution is also recom
mended in patients with pre-existing kidney disease (see WARNINGS - Advanced
Renal Disease).
Hematological Effects: Anemia may occur. In controlled clinical trials the incidence
of anemia was 0.6% with CELEBREX and 0.4% with placebo. Patients on long
term treatment with CELEBREX should have their hemoglobin or hematocrit
checked if they exhibit any signs or symptoms of anemia or blood loss. CELEBREX
does not generally affect platelet counts, prothrombin time (PT), or partial throm
boplastin time (PTT), and does not appear to inhibit platelet aggregation at
indicated dosages (See CLINICAL STUDIES - Special Studies - Platelets in the
complete prescribing information).
Fluid Retention and Edema: Fluid retention and edema may occur (see ADVERSE
REACTIONS). Therefore, CELEBREX should be used with caution in patients with
fluid retention, hypertension, or heart failure.
Preexisting Asthma: Do not use in patients with aspirin-sensitive asthma because
of the risk of severe bronchospasm. Use with caution in patients with preexist
ing asthma.
Laboratory Tests: Because serious GI tract ulcerations and bleeding can occur
without warning symptoms, physicians should monitor for signs or symptoms of
GI bleeding. During the controlled clinical trials, there was an increased incidence
of hyperchloremia in patients receiving celecoxib compared with patients on
placebo. Other laboratory abnormalities that occurred more frequently in the
patients receiving celecoxib included hypophosphatemia, and elevated BUN.
These laboratory abnormalities were also seen in patients who received com
parator NSAIDs in these studies. The clinical significance of these abnormalities
has not been established,
Drug Interactions: General: Celecoxib metabolism is predominantly mediated via
cytochrome P450 2C9 in the liver. Co-administration of celecoxib with drugs that
are known to inhibit 2C9 should be done with caution. In vitro studies indicate
that celecoxib, although not a substrate, is an inhibitor of cytochrome P450 2D6.
Therefore, there is a potential for an in vivo drug interaction with drugs that are
metabolized by P450 2D6. ACE-inhibitors: Reports suggest that NSAIDs may
diminish the antihypertensive effect of Angiotensin Converting Enzyme (ACE)
inhibitors. This interaction should be given consideration in patients taking
CELEBREX concomitantly with ACE-inhibitors. Furosemide: Clinical studies, as
well as post marketing observations, have shown that NSAIDs can reduce the natri
uretic effect of furosemide and thiazides in some patients. This response has been
attributed to inhibition of renal prostaglandin synthesis. Aspirin: CELEBREX can
be used with low dose aspirin. However, concomitant administration of aspirin
with CELEBREX may result in an increased rate of GI ulceration or other compli
cations, compared to use of CELEBREX alone (see CLINICAL STUDIES - Special
Studies - Gastrointestinal in the complete prescribing information). Because of
its lack of platelet effects, CELEBREX is not a substitute for aspirin for cardio
vascular prophylaxis. Fluconazole: Concomitant administration of fluconazole at
200 mg QD resulted in a two-fold increase in celecoxib plasma concentration. This
increase is due to the inhibition of celecoxib metabolism via P450 2C9 by flu
conazole (see Pharmacokinetics - Metabolism). CELEBREX should be introduced
at the lowest recommended dose in patients receiving fluconazole. Lithium: In a
study conducted in healthy subjects, mean steady-state lithium plasma levels
increased approximately 17% in subjects receiving lithium 450 mg BID with
CELEBREX 200 mg BID as compared to subjects receiving lithium alone. Patients
on lithium treatment should be closely monitored when CELEBREX is introduced
or withdrawn. Methotrexate: In an interaction study of rheumatoid arthritis
patients taking methotrexate, CELEBREX did not have a significant effect on the
pharmacokinetics of methotrexate. Warferin: Anticoagulant activity should be
monitored, particularly in the first few days, after initiating or changing CELEBREX
therapy in patients receiving warfarin or similar agents, since these patients are
at an increased risk of bleeding complications. The effect of celecoxib on the anti
coagulant effect of warfarin was studied in a group of healthy subjects receiving
daily doses of 2-5 mg of warfarin. In these subjects, celecoxib did not alter the
anticoagulant effect of warfarin as determined by prothrombin time. However, in
post-marketing experience, bleeding events have been reported, predominantly
in the elderly, in association with increases in prothrombin time in patients receiv
ing CELEBREX concurrently with warfarin. Carcinogenesis, mutagenesis, impair
ment of fertility: Celecoxib was not carcinogenic in rats given oral doses up to
200 mg/kg for males and 10 mg/kg for females (approximately 2- to 4-fold the
human exposure as measured by the AUCo0 24at 200 mg BID) or in mice given
oral doses up to 25 mg/kg for males and 50 mg/kg for females (approximately
equal to human exposure as measured by the AUCo-24at 200 mg BID) for two
years. Celecoxib was not mutagenic in an Ames test and a mutation assay in
Chinese hamster ovary (CHO) cells, nor clastogenic in a chromosome aberration
assay in CHO cells and an in vivo micronucleus test in rat bone marrow. Cele
coxib did not impair male and female fertility in rats at oral doses up to 600
mg/kg/day (approximately 11-fold human exposure at 200 mg BID based on the
AUCo-24).
Pregnancy: Teratogenic effects: Pregnancy Category C. Celecoxib was not ter
atogenic in rabbits up to an oral dose of 60 mg/kg/day (equal to human exposure
at 200 mg BIDas measured by AUCo-24);however, at oral doses 0 150 mg/kg/day
(approximately 2-fold human exposure at 200 mg BID as measured by AUCo_24),
an increased incidence of fetal alterations, such as ribs fused, sternebrae fused
and sternebrae misshapen, was observed. A dose-dependent increase in diaphrag
matic hernias was observed in one of two rat studies at oral doses 30 mg/kg/day
(approximately 6-fold human exposure based on the AUCo-24at 200 mg BID).There
are no studies in pregnant women. CELEBREX should be used during pregnancy
only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic
effects: Celecoxib produced preimplantation and post-implantation losses and
reduced embryo/fetal survival in rats at oral dosages > 50 mg/kg/day (approxi
mately 6-fold human exposure based on the AUCo0 24 at 200 mg BID). These
changes are expected with inhibition of prostaglandin synthesis and are not the
result of permanent alteration of female reproductive function, nor are they
expected at clinical exposures. No studies have been conducted to evaluate the
effect of celecoxib on the closure of the ductus arteriosus in humans. Therefore,
use of CELEBREXduring the third trimester of pregnancy should be avoided. Labor
and delivery: Celecoxib produced no evidence of delayed labor or parturition at
oral doses up to 100 mg/kg in rats (approximately 7-fold human exposure as
measured by the AUCo24 at 200 mg BID). The effects of CELEBREX on labor and
delivery in pregnant women are unknown. Nursing mothers: It is not known
whether this drug is excreted in human milk. Because many drugs are excreted
in human milk and because of the potential for serious adverse reactions in nursing
infants from CELEBREX, a decision should be made whether to discontinue
nursing or to discontinue the drug, taking into account the importance of the drug
to the mother.